Copyright Statement

Abstract

Although respiratory syncytial virus (RSV) is responsible for more human deaths each
year than influenza, its pathogenic mechanisms are poorly understood. Here high-resolution
quantitative imaging, bioenergetics measurements and mitochondrial membrane potential- and
redox-sensitive dyes are used to define RSVís impact on host mitochondria for the first time,
delineating RSV-induced microtubule/dynein-dependent mitochondrial perinuclear clustering, and
translocation towards the microtubule-organizing centre. These changes are concomitant with
impaired mitochondrial respiration, loss of mitochondrial membrane potential and increased
production of mitochondrial reactive oxygen species (ROS). Strikingly, agents that target
microtubule integrity the dynein motor protein, or inhibit mitochondrial ROS production strongly
suppresses RSV virus production, including in a mouse model with concomitantly reduced virus-
induced lung inflammation. The results establish RSVís unique ability to co-opt host cell
mitochondria to facilitate viral infection, revealing the RSV-mitochondrial interface for the first time
as a viable target for therapeutic intervention.